KARMELA KRLEŽA-JERIĆ

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PERIODICUM BIOLOGORUM UDC 57:61 VOL. 116, No 4, 337–339, 2014 CODEN PDBIAD  ISSN 0031-5362  Sharing of clinical trial data and research integrity Imagine that you went to see your family physician with an ailment, and she/he prescribed some medication. After taking it, you devel-oped a nasty reaction, were hospitalized and learned only there and then (if ever) that you should not have been prescribed this particular medi-cation given your other conditions, age or sex. How could that happen? Well, chances are your doctor did not have access to all the information about the medicines prescribed. Oops! Or imagine that you are a re-searcher who spent a few years preparing a study to test a promising new medicine. You then started the clinical trial, and your study participants experienced no effects or serious side-effects. Only then did you learn (if ever) that this particular intervention had proven to be unsuccessful or even harmful in several unreported or currently ongoing studies that you were unaware of. Thus, you wasted several years on a useless or potentially harmful study.Clinical trials* are indispensable in the development of most new and improved medical interventions (1). Integrity in clinical trials seems to be difficult to achieve due to numerous barriers, including the culture of non-sharing of research data. I argue that full transparency of clinical trial data is an essential prerequisite to achieving research integrity, and is equally important as factors such as the initial idea, a high quality research plan and protocol, and the ethically sound conduct of research.In the health field, we (cl)aim to make evidence-informed decisions. This would be phenomenal provided we had reliable evidence; evidence based on all knowledge available at a given moment in time. However, we don�t. Evidence gained by systematic review, meta-analysis of ag-gregate data and pooled analysis of raw data of clinical trials is consid-ered to be the most reliable evidence we can devise for health care deci-sion-making, including for the development of new diagnostics and therapies.Research is continuously getting more powerful largely due to new technologies and related know-how. It benefits from the ever-increasing possibilities offered by digital and cloud-based software technologies, including electronic data management and record keeping that should have enabled faster knowledge creation, and a higher level of efficiency EditorialKARMELA KRLEŽA-JERIĆ Ottawa Group, IMPACT  NewFelPro,  Department of Research in Biomedicine and HealthUniversity of Split School of Medicine,  [oltanska 2, Split, Croatia  http://ottawagroup.ohri.ca/disclosure.htmlE-mail: krlezajk@hotmail.com; Karmela.krleza-jeric@mefst.hr  Received February 16, 2015.         *Clinical trials (also known as interventional studies) are performed on human participants, which can be either healthy volunteers or individuals that suffer from a disease or condition for which diagnostic procedures or therapies are being devel-oped. The intervention, for example, could be that a candidate for a new drug is given to study participants and its effects are measured and compared to the existing medication or to the placebo if there is no existing medication.K. Krleza-Jeric Sharing of clinical trial data and research integrity338 Period biol, Vol 116, No 4, 2014.and integrity of research. Alas, this has been true only to a degree: clinical trial research is burdened with various biases that arise from the non-sharing of research data (1). Research, especially health research, seems to be a hostage to the existing, more or less unchanged fear of sharing data, and of the “it’s mine” and “no data sharing until there is clear and unambiguous proof that no harm will result (especially to me)” culture viewpoint (2). In short, research paradigm changes lag behind the advancements of technology. Numerous benefits are anticipated from increasing the sharing of clinical research data: it accelerates the develop-ment of new knowledge and innovation, enhances trans-lational research, informs decision-making and helps ensure the efficiency and integrity of research. Specific benefits include avoiding unnecessary and redundant re-search and thus decreasing the burden on research par-ticipants. On the other hand, there is increased awareness of the harm caused by the non-sharing or partial sharing of such data.I want to believe that researchers aim to perform meaningful and efficient research, which is ethically and economically sound and contributes to the common good. Thus I expect that any given researcher would take advantage of existing tools to develop, conduct, and re-port high quality and efficient trials. These tools include systematic reviews to capture the existing knowledge, SPIRIT guidelines (3) for protocol development, ethics approvals guaranteeing the respect of study participants’ wellbeing, and CONSORT guidelines (4) for the publica-tion of summaries of findings. WHO International standards define trial registration, and its International Clinical Trials Registry Platform links to the basic protocol information hosted by a net-work of WHO trial registries. One of these registries, Clinicaltrials.gov, also accepts results in aggregate data format. Supported by journal editors (5, 6), funders, the Ottawa group, All Trials initiative and others, and en-forced by national legislations, trial registration is gradu-ally becoming an integral part of the clinical trial process.The next step is to complement trial registration with results disclosure, publication of findings and public dis-closure of all data, including raw data; i.e. individual par-ticipant data (IPD). However, although there are reposi-tories that host clinical trial data, the methodology for preparation of data for public release and reuse is still under development and no standards exist. Researchers need to know what the analysable data set consists of and where to deposit it, which calls for the development of methodology and standards to guide data preparation for public release and re-analysis. Such datasets would in-clude anonymized IPD, metadata, dictionary (descrip-tors) and more; presented in a structured format, which should follow certain standards across repositories. Initiatives aimed at opening clinical trial data have been taking place in many parts of the world in various forms (7, 8). The strength of this movement is that it brings together people from various fields, including data managers, scientists and knowledge users.The abundance of research and the benefits that re-searchers seek from it have led to increased concerns for research integrity and responsible research. There are nu-merous scientific, practical, legal and ethical issues that prevent the achievement of fully responsible and efficient research. Physician clinical trialists are also bound by the Hippocratic Oath and its “do no harm” principle, as well as the promise that “the health of my patient will be my first consideration…” The Declaration of Helsinki (9) is increasingly calling for trial registration and sharing of results, as is the World Health Organization. Offices of research integrity have been formed, and the World Con-ference on Research Integrity produces statements aiming at increasing the integrity in research. An issue of par-ticular concern is that of data sharing. Public disclosure of data would not only facilitate the verification of pub-lished information and increase the speed of knowledge creation, but it would also contribute to the prevention of other research integrity issues such as plagiarism and fraud.Interest in broader sharing of research data is increas-ing and many initiatives are underway. In the clinical trial field, notable recent efforts include the US Institute of Medicine (IOM) recommendations  on sharing clinical trial data (10), the European Clinical Trial Regulations (11) as well as policies of the European Medicine Agency (EMA) (12) that will enable access to clinical trial reports as of January 2015. Many, including the Ottawa Group and its IMPACT Initiative, are looking for methods and standards for the public disclosure of trial data and re-lated repositories.The field is so complex that it would merit structured monitoring of the impact of changes in data sharing on clinical trials in order to connect dots and indicate trends. The recently started IMPACT Observatory (natural ex-periment) aims to do just that. Overall understanding of the advantages of open data and open science is increasing. New technological op-portunities are enabling the analysis of big data sets with new algorithms. This does not only serve the purpose of verifying whether a report is biased, but the reanalysis of several trials can lead to more findings. The clinical trial field is not isolated in this evolution of research; it could learn a lot from other areas as many are more advanced. However, there is insufficient communication of experi-ence with data sharing among scientific fields, which again might be due to its novelty and dynamics. The opening of oncology clinical trials data is particu-larly important as it would contribute to the desperately Sharing of clinical trial data and research integrity K. Krleza-JericPeriod biol, Vol 116, No 4, 2014. 339needed increase in knowledge and innovation, which is essential to in the fight against cancer. One example of data sharing initiatives in oncology is the CEO Round-table on Cancer and its Project DataSphere (PDS) as it aims to brings together private, public and not-for-profit organizations to fight cancer. In 2014, following several years of preparation, the CEO launched the DataSphere platform of oncology with the goal of gradually making oncology data available for further research, to “share, integrate and analyse” and thus speed up the development of new therapies. The vast majority of clinical research data is still not open but rather is of limited access, including semi-open data sharing, sharing within certain groups, sharing pre-competitive data only, and sharing for research purposes only, upon request or by agreement. The opening of clinical trial data would enhance the efficiency and responsibility of research, and contribute to strengthening or even regaining people’s trust in re-search and medicine. It has been emphasized over and over again that we have to do whatever it takes to over-come the remaining barriers in opening clinical trial data as we primarily owe it to trial participants. After all, they are the ones who take a risk by participating in the clini-cal trials that enable data gathering to begin with.Acknowledgements:  I would like to thank Karine Morin, Pavle Jerić, and Jasmine Lefebre for comments on earlier version of this manuscript.REFERENCES 1.  CHAN A-W 2012 Out of sight but not out of mind: how to search for unpublished clinical trial evidence. BMJ 344: 8013 doi:10.1136/bmj.d8013. 2.  VICkERS A J 2006 Whose data set is it anyway? Sharing raw data from randomized trials. Trials  7: 15 3.  CHAN A-W, TETzLAff J M, ALTMAN D G, LAUPACIS A, GøTzSCHE P C, kRLEžA-JERIć k, HRóBJARTSSON A, MANN H, DICkERSIN k, BERLIN J A, DORé C, PARULEk-AR W, SUMMERSkILL W S M, GROVES T, SCHULz k, SOx H, ROCkHOLD f W, RENNIE D, MOHER D 2013 SPIRIT 2013 Statement: Defining standard protocol items for clinical trials. Ann Intern Med 158: 200-207 4.  SCHULz k f, ALTMAN D G, MOHER D, CONSORT Group 2010 CONSORT 2010 Statement: Updated Guidelines for Report-ing Parallel Group Randomised Trials. PLoS Med 7(3): e1000251. doi:10.1371/journal.pmed.1000251 5.  LAINE C, HORTON R, DEANGELIS C D, DRAzEN J M, fRIzELLE f A, GODLEE f, HAUG C, HéBERT P C, HOR-TON R, kOTzIN S, MARUSIC A, SAHNI P, SCHROEDER T V, SOx H C, VAN DER WEYDEN M B, VERHEUGT f W 2007 Clinical trial registration: looking back and moving ahead. Editorial. Ann Intern Med 147(4): 275-7 6.  MARUšIć A, HUIć M 2008 Registration of Clinical Trials Still Moving Ahead – September 2008 Update to Uniform Require-ments for Manuscripts Submitted to Biomedical Journals. Croat Med J  49(5): 582–585. doi:  10.3325/cmj.2008.5.582  7.  kRLEžA-JERIć k, LEMMENS T, REVEIz L, CUERVO L G, BERO L A 2011 Prospective registration and results disclosure of clinical trials in the Americas: A roadmap toward transparency. Revista Panamericana de Salud Publica/Pan American Journal of Public Health 30: 87-96 8.  zARIN D A 2013 Participant-level data and the new frontier in trial transparency [editorial]. N Engl J Med 369(5): 468-9 9.  kRLEžA-JERIć k, LEMMENS T 2009 7th revision of the Dec-laration of Helsinki: Good News for the Transparency of Clinical Trials. Croat Med J  50: 105-11010.  IOM (Institute of Medicine). 2015 Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk. National Academies Press ,Washington, DC Available from:  http://www.iom.edu/Reports/2015/Sharing-Clinical-Trial-Data.aspx (accessed 30 January 2015)11.  European Commission; Medicinal Products for Human Use 2014 Clinical trials - Regulation EU No 536/2014. Available from: http://ec.europa.eu/health/human-use/clinical-trials/index_en.htm (accessed 17th Feb 2015)12.  European Medicines Agency 2014 European Medicines Agency policy on publication of clinical data for medicinal products for human use.  Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/WC500174796.pdf (accessed 2015-2-15)

Sharing of clinical trial data and research integrity

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